DESCRIPTION (Scanned from the Applicant's Abstract): Obesity is the most common contributing factor to illness worldwide, including such diseases as Type II diabetes, coronary heart disease and cancer. Although the molecular basis for obesity is still unknown, recent research has provided evidence which demonstrated that melanocortins play a prominent role in regulating energy balance. Results from murine genetic experiments, in which the melanocortin-3 receptor gene has been disrupted, suggests that this receptor may play a unique regulatory role in overall energy metabolism of these animals. Thus, we propose to initiate a series of studies to explore the pharmacology of this receptor and its role in obesity. Initially, we will use a MC3-R selective peptide modulator, gamma-melanocyte stimulating hormone, to test its effect on energy balance in obese mice. In parallel, we also propose to initiate a focused high-throughput combinatorial chemistry approach to identify small organic molecules designed to stimulate the MC3 receptor, as well as selective antagonists, in order to provide better pharmacologic tools. If our results confirm that activation of MC3-R does not effect appetite, but rather influences energy partitioning and metabolism, the small molecule agonists identified in Phase I of this study could serve as chemical leads for a novel class of anti-obesity therapeutics. PROPOSED COMMERCIAL APPLICATION: We are proposing to develop a small molecule agonist of the melanocortin-3 receptor. This receptor has been shown to play a key role in regulating the amount of body fat and energy balance. Thus, an MO receptor agonist may be a novel approach toward preventing obesity and its co-morbidities, and could provide an important novel class of human therapeutic agents.